Description (Adapted from the applicants' abstract): Mast cells are functionally versatile and anatomically ubiquitous elements of the immune system with well established roles in allergy and immunology. Mast cells are capable of modulating the hosts' innate immune defense against gram negative bacteria by augmenting the influx of neutrophils at sites of infection through the release of TNF (Nature, 381: 77-80, 1996). Further mast cell-bacteria interactions are mediated by the mast cell surface receptor CD48 and bacterial adhesion molecule FimH. JAK-3-deficient mast cells and JAK-3-deficient mice have reduced capacity to fight gram negative bacteria. The hypothesis to be investigated is that specific biochemical signal transduction events involving the protein tyrosine kinase JAK3 are triggered by mast cell-gram negative bacteria interactions. Mechanistic studies are proposed to further elucidate the role of mast cells in host defense. To this end, the PI will test specific hypotheses using well-established in vitro and in vivo model systems. Specific Aim #1 will test the ability of mast cells to mount a response against gram negative bacterial infections, and will characterize the signal transduction events triggered by the interaction of gram negative bacteria with mast cells. Under Specific Aim 2, the PI will attempt to translate this knowledge into a new strategy for more effective treatment of gram negative bacterial infections based upon cytokine stimulated potentiation of mast cell defenses against gram negative bacterial infections. Specifically, the in vitro and in vivo effects of stem cell factor (SCF), a stimulator of the JAK-STAT pathways, on mast cell responses against FimH positive gram negative bacteria will be examined. These studies will provide new insights regarding the participation of mast cells in innate host defense against pathogenic gram negative bacteria.